Sulfates of steroids, for example, dehydroepiandrosterone sulfate, cholesterol sulfate, estrone sulfate and the like are intermediate metabolites of steroid within the human body. These sulfates are metabolized into still other steroids in living body. For example, estrone sulfate is hydrolyzed with steroid sulfatase which is present in living body into free estrone which is further reversibly converted to estradiol, with 17β-hydroxysteroid dehydrogenase. These estrogens such as estrone, estradiol and the like which are formed through steroid metabolism are closely associated with such diseases as breast cancer, uterine cancer, ovarian cancer, endometriosis, adenomyosis uteri, mastopathy and the like.
Therefore, effective inhibition of steroid sulfatase activity is expected to be useful for therapy of diseases associated with steroids such as estrogen or androgen, and in line with this concept a number of steroidal compounds which exhibit steroid sulfatase-inhibitory activity, represented by estrone-3-sulfamate (EMATE) have been proposed (cf. PCT International Publication WO 93/05064 Pamphlet).
However, EMATE is a compound inadequate as a therapeutic agent for estrogen-related diseases, because it exhibits also potent estrogenic activity concurrently with potent steroid sulfatase inhibiting activity.
As non-steroidal compounds having steroid sulfatase inhibiting activity, furthermore, a certain kind of coumarin derivatives, e.g., 4-methylcoumarin-7-sulfamate (COUMATE) (cf J. Med. Chem., Vol. 37, 219 (1994)) and a certain kind of phenyl sulfamate derivatives, e.g., 4-(2-myristoylaminoethyl)phenyl sulfamate (DU-14) have been proposed (cf. J. Med. Chem., Vol. 39, 1349 (1996)).
However, these non-steroidal compounds such as COUMATE or DU-14 exhibit low level of steroid sulfatase inhibiting activity which is the main activity, although they are free from estrogenic activity as a side action, and are not yet quite satisfactory.
The present inventors have recently proposed a certain kind of substituted biphenyl sulfamate derivatives which exhibit potent steroid sulfatase inhibiting activity and yet show no estrogenic activity (cf. PCT International publication WO 01/02349 Pamphlet), but have now found that many of these biphenyl type sulfamate derivatives have genetic toxicity.
We have further pursued our research concentratively to now discover that novel cyclicamino-phenyl sulfamate derivatives or salts thereof in which 4-position of the phenyl group is substituted with a cyclic amino group, i.e., piperidinyl group or piperazinyl group, exhibit excellent steroid sulfatase inhibiting activity and yet are free of estrogenic activity and genetic toxicity. The present invention is whereupon completed.